Pharmaceutical tablet excipients of solid particles of a binary solid solution of mannitol with a sugar



United States Patent Ofifice 3,341,415 Patented Sept. 12, 1967 3,341,415PHARMACEUTICAL TABLET EXCIPIENTS F SOLID PARTICLES OF A BINARY SOLID SO-LUTION 0F MANNITOL WITH A SUGAR Morton W. Scott, Livingston, NJ.,assignor to Warner- Lambert Pharmaceutical Company, Morris Plains, NJ.,a corporation of Delaware No Drawing. Filed Feb. 12, 1964, Ser. No.344,253 12 Claims. (Cl. 167-82) This invention relates to a method forthe preparation of new pharmaceutical excipients. More particularly, thepresent invention relates to a method for the preparation of solidsolutions of mannitol with various sugars for use as a suspending agentor carrier for drug formulations, and to the resulting products.Specifically, the present invention relates to a method of preparingspray congealed binary, ternary, and quaternary solid solutions ofmannitol and various sugars for use as a diluent or carrier for variousdrug formulations and to therapeutic tablets formed therewith.

Mannitol is a well-known hexahydric alcohol which is employed in thepharmaceutical industry as a filler for use in formulating tablets,lozenges, troches and the like primarily because of the desirable tasteand for the smooth texture it imparts to the formulation. One of thedifficulties experienced when including mannitol in pharmaceuticalformulations is that it hinders the free flow of the formulation such aswhen the formulation is fed to the dies of .a tablet press during theformation of tablets. This poor flow results, for the major part, as aresult of the needlelike shape of mannitol crystals. Also, mannitol inthe form commercially available, does not possess satisfactorycompression characteristics and therefore cannot be effectively used asan excipient in concentrations normally required in the manufacture ofsatisfactory tablets on a production basis without recourse to involvedand costly precompression operations such as granulating procedures.

Involved and time-consuming granulation procedures are usually requiredas well as appreciable quantities of tabletting lubricants in order toovercome difiiculties encountered when mannitol is employed as acomponent in the manufacture of tablets. Although such expedients are ofaid in producing acceptable tablets, the involved manipulativeprocedures greatly limit the economical reasons for using mannitol. Inaddition, when such processing expedients are employed, some undesirableimpairment in stability of the active constituents which may be presentin the tablets usually result during the commercial manufactureprocedures.

It is an object of this invention, therefore, to provide a method forthe preparation of a pharmaceutical excipient containing mannitol incombination with certain sugars whereby the physical characteristics ofthe mannitol are desirably modified and improved.

Itis also an object of this invention to provide new pharmaceuticalexcipients formed by pulverizing a solid solution of mannitol andcertain sugars.

It is another object of this invention to provide a method for thepreparation of a pharmaceutical excipient from spray congealed binary,ternary, and quaternary solid solutions of mannitol with certain sugarswhereby the physical characteristics of the mannitol are desirablymoditied and substantially improved for use as a carrier or suspendingagent.

It is a further object of this invention to provide new pharmaceuticalexcipients formed from spray congealed solid solutions of mannitol andcertain other sugars such that the flow and the compressibilitycharacteristics of the mannitol are desirably modified and improved foruse as particles can be conveniently enges, troches, and the like.

These and other objects may be realized by the practice of the presentinvention which generally provides a method for the preparation of newand useful pharmaceutical excipients which are formed from a moltenmixture of prescribed proportions of mannitol in combination withcertain sugars. The formed molten mixture is thereafter rapidly cooled,or more desirably, spray congealed to form particles having asubstantially uniform composition.

In the practice of this invention, the binary, ternary, and quaternarysolid solutions of mannitol may be prepared by blending in asolid'solution, prescribed amounts of mannitol with various sugars, suchas lactose, sucrose, erythritol, galactose, dulcitol and the like.Glycerine and the various glycols may also be incorporated with mannitolin the blends formed with these sugars.

The sugars used to form solid solutions with mannitol may be employed inany desirable proportion. However, the lower melting point mixtures aregenerally preferred along with those in which mannitol comprises atleast about 20 percent by weight of the mixture. Usually, a combinationcontaining the blend formed by the mixture of mannitol and varioussugars may be heated under mild stirring conditions until a moltensolution is formed. The molten solution of these ingredients is thenremoved from the heat and rapidly cooled. The cooled. product, after ithas been reduced to the desired particle size, may be combined withadded active ingredients, as desired, and thereafter formed intotablets, capsules, and the like. Alternately, the active ingredients maybe combined with the mannitol blend in the molten state and the mixturethereafter rapidly cooled and processed into tablets or any otherconvenient form suitable for consumption.

The binary, ternary, and quaternary mixtures of mannitol, as preparedherein, may be rapidly cooled, such as for example, by allowing a moltensolution thereof to flow onto a cool plate which is maintained at atemperature well below the solidifying temperature of the mannitolsolution. The preferred particle size of the solid solution of mannitolformed by this procedure for use in tabletting procedures is generallyabout 12 to about 60 mesh (U.S. Sieve).

More desirably, however, the binary, ternary, and quaternary mixtures ofmannitol, as prepared herein, may be spray congealed by feeding themolten. mixture to an atomizing device such as a pressure nozzle orcentrifugal wheel atomizer to break the molten mixture into smallparticles which are rapidly cooled in a dry inert substantially gaseousatmosphere such as air, nitrogen, helium, and the like, which congealsthe mannitol mixture without any material degree of reaction therewith.

The temperature of the dry-gaseous atmosphere employed may be at anydesirable temperature such .as, for example, from about -10 C. to about810 C., although higher and lower temperatures may be employed. Uponcontact with the gases of the inert atmosphere the finely divided moltenmannitol mixture forms substantially the dry and free-flowing particlesconsisting of a solid solution of mannitol with the various sugarsemployed. The formed particles may then be combined with variousadditives usually employed in tablet compositions.

When the molten mannitol solution is spray congealed by being fed to a5.0 cm. diameter centrifugal atomizer wheel rotating at a speed of from15,000 to 40,000 rpm, the resulting particles are found to have anaverage particle size of about 15 to about 300 microns in diameter.Larger prepared in average sizes up to about 2,000 microns in diameterby using a larger diameter atomizer wheel operating at lower speeds.These particles of the spray congealed mixtures are particularlyvaluable as they permit compositions formed therewith to flow freelysuch as to the feed of a tablet press or filling machine.

Since the melting point or the congealing point of the solid mannitolsolutions prepared herein are relatively high compared to roomtemperature, the molten mannitol solutions will congeal rapidly uponcoming in contact with a cold surface where the temperature of the meltdrops below the congealing temperatures. Therefore, in order to preventany buildup of the solid mannitol solution on the apparatus prior toatomizing, the various parts of the apparatus which contact the moltenmannitol solution and precede the atomizing device must be controllablyheated either electrically or by controlled circulating hot air. The useof temperature substantially above the congealing point of the mannitolsolution are undesirable as such temperatures may have a detrimentaleffect upon any of the constitutents added to the molten mannitolsolution.

Pharmaceutical agents may be combine-d directly with the molten binary,ternary, and quaternary mannitol solutions. However, because manypharmaceutical agents are heat sensitive, there is added advantage inusing the solid solutions of a mannitol of lower melting points.Medicaments which are immiscible in the molten mannitol blend and whichdo not decompose therein are particularly useful and include materialssuch as magnesium trisilicate, calcium carbonate and aluminum hydroxideand the like. Medicaments which are miscible in the molten mannitolsolutions and which do not decompose therein are also useful and includematerials such as p-hydroxy acetanilide, barbital, phenobarbital,amobarbital, phenobarbital sodium diphenhydramine, procainehydrochloride, metycaine, phenylephrine hydrochloride, sulfanilamide,sulfacetamide, and the like. Thereafter, the solutions may be spraycongealed to form small particles of a substantially uniform compositionwhich may be readily compressed into tablet form. As an alternateprocedure, the pharmaceutical excipients containing mannitol may becooled on an ointment mill and then broken up to form smaller sizedparticles. Various heat sensitive therapeutic agents may then be addedto the mannitol solid solutions prior to forming tablets, capsules andthe like.

The following examples are included further to illustrate thisinvention.

Example 1 Twenty grams of mannitol are melted in an electrically heatedlaboratory mixer and 20 grams of sucrose are gradually added to themolten mannitol with continuousmixing. When the mannitol and sucrose areblended, the blend is removed from the mixer and cooled to form a solidsolution of sucrose and mannitol which has a melting point of about 150C. The congealed mass is then passed through a micropulverizer, whereinnon-spherical particles are formed. One gram of magnesium stearate isblended with the pulverized mass and the final product has an averageparticle size of about 12 to about 60 mesh. (U.S. Sieve) A secondmixture is made by melting 20 grams of mannitol in an electricallyjacketed laboratory mixer to which 20 grams of sucrose are added. Theliquid mannitol sucrose mixture is then spray congealed by employing arotating wheel atomizer of 5.0 cm. diameter operating at about 35,000rpm. and by directing the spray into a flowing stream of air maintainedwith an inlet temperature of 25 C. The particles formed are found to besubstantially uniform with an average particle size of from about 50 toabout 260 microns in diameter.

For comparison, a third test sample is prepared by mixing twenty gramsof powdered sucrose with an equal amount by weight of powdered mannitoland then thoroughly blending one gram of magnesium stearate in thisblend of powdered mannitol and sucrose. The powdered mannitol andsucrose employed have a particle size of 50 to 200 microns.

When the sample formed by blending equal amounts of powdered sucrose andpowdered mannitol and then adding magnesium stearate (third test sample)is compressed in a Stokes E single punch press using standard concavepunches, the mixture is observed to have poor flow properties ascompared to the particles formed of the solid solutions of the first andsecond test sample. Further, the sucrose-mannitol mixed powder exhibitspoor compressibility with sticking and binding occurring in the moldwhen tablets with a hardness of 8 Strong-Cobb units were desired. Theparticles of sucrosemannitol solid solution prepared in the first areobserved to have good flow properties and exhibited good compressibilityup to about 10 Strong-Cobb units without excessive sticking and bindingoccurring in the mold.

The spray congealed particles of the sucrose-mannitol solid solution areobserved to have excellent flow properities and exhibit excellent tabletcompressibility up to 12 Strong-Cobb units without sticking, capping, orbinding occurring in the mold.

Example 2 Thirty grams of mannitol are melted in an electrically heatedmixer and seventy grams of dulcitol are then gradually added to themolten mannitol with continuous mixing. When the mannitol and dulcitolare thoroughly blended, the blend is removed from the mixer, cooled, andthe cooled mass then passed through a micropulverizer wherein particleshaving an average particle size of about 12 mesh (U.S. Sieve) areproduced. The powder obtained melts at a temperature 156-158 C. One gramof magnesium stearate is added and then blended into the micropulverizedmass. Tablets are formed from this blend by the tabletting procedure ofExample 1. The lubricating particles of the mannitol-dulcitolsolid'solution exhibit excellent flow properties. The tablets are formedwithout capping, sticking or binding and may be produced in a range upto 10 Strong-Cobb units.

Example 3 The procedure of Example 2 is repeated using a blend of gramsof erythritol with 20 grams of mannitol. This combination is found toproduce a blend melting at 114- 118 C. Tablets which are formed on usingthis mixture reduced to a particle size of about 12 mesh (U.S. Sieve)and the tabletting procedure of Example 1 are found to have good fiowcharacteristics with excellent compressibility up to 10 Strong-Cobbhardness units.

Example 4 The procedure of Example 2 is repeated using a blend of 20grams of lactose with 80 grams of mannitol. This weight combination isfound to melt at about 162 C. The molten solution is spray-congealed bythe atomizing and cooling procedures employed in Example 1. Tabletsformed using the above solid solution in particles of 50 to 260 micronsin diameter in the tabletting procedure of Example 1 are satisfactoryand the blend is found to have good flow characteristics with excellentcompressibility to form tablets of up to 10 Strong-Cobb hardness units.

Example 5 The procedure of Example 2 is repeated using 20 grams ofgalactose and 80 grams of mannitol. This weight combination is found tomelt at about 156 C. Tablets formed using this mixture and thetabletting procedure of Example 1 are found to have good flowcharacteristics with excellent compressibility up to 10 Strong-Cobbhardness units.

Example 6 Eighty grams of mannitol are melted in an electrically heatedmixer and maintained slightly above the melting point of mannitol orabout 167 F. Eighty grams of sucrose are dissolved in the moltenmannitol along with 40 grams of magnesium trisilicate. This moltensolution is thereafter spray congealed into an atmosphere of cool dryair maintained at 30 C. employing a rotating wheel atomizer. Theparticles, having an average size of 50 to about 260 microns indiameter, are combined with 4 grams of calcium stearate and tablets areformed of the mixture on a standard rotating tablet press.

The spray congealed mixture is found to have substantially improved flowcharacteristics over equivalent dry mixtures obtained by blending finelydivided mannitol, sucrose, and magnesium trisilicate of equivalentparticle size. The flow characteristics are found to be far superior toa dry mixture containing only mannitol and phenobartital. The tabletsformed with this spray congealed mixture are found to exhibit excellentcompressibility characteristics without capping, sticking or binding.

Example 7 The procedure of Example 4 is repeated using 20 grams ofsulfanilamide in a molten mixture of 30 grams of mannitol and 70 gramsof dulcitol. The molten mixture is spray congealed following theprocedure described in Example 4. About 0.6 gram of calcium stearate isadded to and blended with the spray congealed particles. Tablets arereadily formed in a standard tablet press with no apparent capping orchipping, nor are the tablets friable. These tablets formed are found tohave a disintegration time of about 50 minutes when there is nodisintegrant added.

Example 8 The procedure of Example 4 is repeated using 20 grams ofmannitol and 80 grams of erythritol. When the solution is molten, 20grams of dicyclomine hydrochloride are added and the solution is spraycongealed to form particles of an average particle size of about 50 toabout 260 microns in diameter which are then combined with 2.5 grams ofcalcium stearate and sodium diphenhydramine. Tablets are formed in astandard tablet forming machine. There is no apparent capping, sticking,or binding. Tablets similarly processed containing powdered mannitol andsodium diphenhydramine are found to stick in the press even atsubstantially lower pressure than those used to form tablets by thepresent example.

Example 9 A ternary mixture is formed by melting 60 grams of mannitoland then adding 20 grams of sucrose and 30 grams of lactose to the melt.Twenty grams of aluminum hydroxide are blended with the molten mixturewhich is thereafter spray congealed. The particles formed are found tohave a particle size of 50 to 260' microns in diameter. About 1 /2 gramsof calcium stearate are blended with the particles of the spraycongealed ternary mixture. This blend exhibits excellent flowcharacteristics when fed to a standard press and the tablets formed showno substantial capping, sticking or binding in the cavities.

Although the binary and ternary mixture of mannitol are specificallydescribed herein for use as pharmaceutical tabletting excipients, thesemixtures may also be used in the preparation of confections, powderedconcentrates and the like. Other uses will also become apparent such asthose wherein mannitol sugars are customarily employed.

Magnesium stearate, calcium stearate, sodium stearate, stearic acid,talc, and the like lubricants may be usefully employed to facilitatetabletting of compositions containing the pharmaceutical excipients asprepare-d herein.

If desired, other additives such as fillers, stabilizers, coloring andflavoring ingredients may also be combined with the describedpharmaceutical excipients to impart any desired added characteristics tothe formed tablets.

It is to be understood that the foregoing detailed description is givenmerely by way of illustration and that many variations may be madetherein without departing from the spirit of the present invention.

What is claimed is:

1. In a method of forming a tabletting excipient containing mannitol asan essential ingredient for use in compression tabletting, theimprovement which consists essentially of forming solid particles of abinary solid solution of mannitol with a sugar.

2. In a method of forming a tabletting excipient containing mannitol asan essential ingredient for use in compression tabletting, theimprovement which consists essentially of atomizing a molten solution ofmannitol and a sugar in the form of finely divided droplets into astream of an inert gas and congealing the droplets to form finelydivided particles having nearly spherical particle shape.

3. In a method of forming a tablet excipient containing mannitol as anessential ingredient for use in compression tabletting, the improvementwhich consists essentially of forming solid particles of a binary solidsolution of mannitol with a sugar, said particles having an averageparticle size or from about 15 microns in diameter to about 2,000microns in diameter and formed by spray congealing a molten solution ofmannitol with a sugar in the form of finely divided particles into astream of inert gases.

4. In a method of forming a tabletting excipient containing mannitol asan essential ingredient for use in compression tabletting, theimprovement which consists essentially of forming solid particles of abinary solution of mannitol with a sugar selected from the group consisting of lactose, sucrose, erythritol, galactose, and dulcitol.

5. In a method of forming a tabletting excipient containing mannitol asan essential ingredient for use in compression tabletting, theimprovement which consists essentially of forming solid particles of aternary solid solution of mannitol and a sugar selected from the groupconsisting of sucrose, dulcitol, erythritol, lactose, and galactose.

6. In a method of forming a tabletting excipient containing mannitol asan essential ingredient for use in compression tabletting, theimprovement which consists essentially of forming solid particles of aquaternary solid solution of mannitol and a sugar selected from thegroup consisting of sucrose, dulcitol, erythritol, lactose andgalactose.

7. A method for the preparation of new improved therapeutic tabletswhich comprises heating a mixture of mannitol and sucrose to a moltensolution, blending a medicament therein, spray congealing the mixture toform compressible granules and compressing said granules into a tablet.

8. A method for the preparation of new improved therapeutic tabletswhich comprises, heating a mixture of mannitol and erythritol to amolten solution, blending a medicament therein, spray congealing themixture to form compressible granules and compressing said granules intoa tablet.

9. A method for the preparation of new improved therapeutic tabletswhich comprises, heating a mixture of mannitol and lactose to a moltensolution, blending a medicament therein, spray congealing the mixture toform compressible granules andcompressing said granules into a tablet.

10. A method for the preparation of new improved therapeutic tabletswhich comprises, heating a mixture of mannitol and galactose to a moltensolution, blending a medicament therein, spray congealing the mixture toform compressible granules and compressing said granules into a tablet.

11. A method for the preparation of new improved therapeutic tabletswhich comprises, heating a mixture of mannitol and dulcitol to a moltensolution, blending a medicament therein, spray congealing the mixture toform 7 compressible granules and compressing said granules into atablet.

12. A method for the preparation of new improved therapeutic tabletswhich comprises, heating a mixture of mannitol, sucrose, and lactose toa molten solution, 5

blending a medicament therein, spray congealing the mixture to formcompressible granules and compressing said granules into a tablet.

References Cited UNITED STATES PATENTS 4/1963 Tuerck et a1. 167-828/1964 Lieberman et al 16782 LEWIS GOTTS, Primary Examiner.

S. K. ROSE, Assistant Examiner.

1. IN A METHOD OF FORMING A TABLETTING EXCIPIENT CONTAINING MANNITOL ASAN ESSEENTIAL INGREDIENT FOR USE IN COMPRESSION TABLETTING, THEIMPROVEMENT WHICH CONSISTS ESSENTIALLY OF FORMING SOLID PARTICLES OF ABINARY SOLID SOLUTION OF MANNITOL WITH A SUGAR.